JPH01313430A - Water-soluble preparation of coccidium inhibitor - Google Patents

Abstract

PURPOSE: To obtain a stable active preparation useful for the prophylaxis and treatment of coccidiosis and capable of being administered to farm animals together with drinking water by compounding a specific coccidiostat under specific conditions. CONSTITUTION: This preparation is obtained by compounding one or more kinds selected from coccidiostats of formula I [R<1> is H or a 1-4C alkyl; R<2> and R<3> together form a double bond, or area each H or a 1-4C alkyl; R<3> and R<2> together forma double bond, etc.; X is F, Cl, Br, etc.; (n)=0-4; Y is H, a 1-6C alkyl, etc.; Z is a direct bond, O, S, etc.] and formula II (R'=R; W is O or S) in an amount of up to 10000ppm based on the total weight of the preparation with a water-miscible anionic or cationic surfactant or their mixture, and a water-soluble organic solvent in an amount of 0-80wt.% and water in an amount of 0-70wt.%, each based on the total weight of the preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a liquid formulation of a coccidia inhibitor that can be administered to livestock with drinking water or the like. .

General formulas (1) and (■): [In the formula, R1, R and R' are each independently hydrogen or 01-C4-alkyl. R2 together with R5 represents a double bond or itself independently is hydrogen or 01-C4-alkyl; R3 together with R2 represents a double bond or itself independently is hydrogen or O1-C4-alkyl, W is oxygen or sulfur, and X is each independently halogen such as fluorine, chlorine and bromine, C1-C4-alkyl, trifluoromethyl, cyano, Thiocyanato, 01-C4-alkylthio,
nitro or 01-C4-alkoxy, n is 0.1.2.3 or 4, preferably 0-2, Y is hydrogen, C1-C6-alkyl, 01-C6-halogenoalkyl, benzyl, phenyl , or at least one group selected from the group consisting of alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, halogen, alkylthio, alkylsulfinyl, alkylsulfonyl, halogenoalkylthio, halogenoalkylsulfinyl, and halogenoalkylsulfnyl where each alkyl group is phenyl substituted with 1 to 4 carbon atoms, or thienyl or herochenyl, and Z is a direct bond or has the formula ○, S, 5O1so2,
NH, NR [] (However, RO is hydrogen or C1-C4-
alkyl) or a divalent group of C(CN(R+
) (where R+ is hydrogen or methyl)] of]N-
Fuphenylazide has been disclosed as an active substance against coccidiosis and similar diseases in livestock (
For example, European Patent Application Publication No. 0,215,354, 0
．． No. 154,885 (U.S. Patent Application No. 4,640,917
No.), No. 0,170,316 and No. 0,232,9
2, and West German Patent Application Publication No. 2,413,722
Nos. 2,718,799 and 2,722,537 (U.S. Patent Application No. 4,198,407) and U.S. Pat. No. 905,971).

For the treatment of coccidiosis, until now it has been necessary to add active substances in solid crystalline form to livestock feed. No form has hitherto been found that is generally suitable for use in administration through drinking water. On the other hand, administration via drinking water if possible is the most ideal method for livestock keepers, especially for managing active livestock (= is the preferred method).

That is, for example, livestock infected with coccidiosis often refuse to consume feed, but will still readily try to consume drinking water. It is therefore usually difficult or impossible to treat coccidiosis via feeds containing active substances.

To ensure reliable administration through drinking water, the active substance must be homogeneously dispersed in the water and present in a stable and effective form. The active substances of formula (I) and (II) are insoluble in water. The concentration used varies depending on the species and severity of the disease, usually 1-500 ppm, preferably 22-10
0 ppm: especially 2 to 30 ppm, but the above-mentioned substances are completely or partially precipitated out of the suspension prepared at this concentration even during use.

The period of use varies depending on the condition of the livestock being fed.

However, the potable water to which the active substance has been added must form a stable aqueous solution or suspension for at least 24 hours, and if possible for longer than 24 hours. That is,
As coccidial inhibitors of formulas (1) and (If), they are stable during this time and cannot be prepared in aqueous form with a defined concentration of active substance without auxiliaries.

The active substances of formulas (1) and (II) can be used in various organic solvents,
For example, acetone, alcohol, dimethyl sulfoxide, ethyl acetate or N-methylpyrrolidone (=) dissolves easily. However, when these solutions are diluted with water to the dosage concentration, the active substance precipitates again immediately or within a short time. I end up analyzing it.

West German patent application No. 3.300.793 states that R is hydrogen and -
14=, R' is methyl, n is 1, X is 3-methyl, W is 0 and Y-Z is 4-trifluoromethylthiophenoxy (1 ) are disclosed. These solutions of active substances containing one or more polar solvents and alkaline-reactive substances can be diluted with water to a dosage concentration of active substance of 24.
The active substance does not precipitate within hours.

This method for preparing active substances as stable aqueous solutions is not applicable to active substances of formula (I).

West German patent 3.300.79! No. 1 further states that solubilization in an aqueous medium by adding solubilizing agents, such as polyoxyethylated castor oil or polyoxyethylene sorbitan fatty acid esters, has been successful in the case of active substances of the formula (In). It is disclosed that the precipitation of the active substance can be delayed for several hours, but not for up to 24 hours.

In addition, normal concentration, that is, concentration that does not interfere with use (0,5
It is also not possible to dissolve the active substance of formula (D) at the required dosage concentration in water containing solubilizers (~5% by weight).

Thus, there is a need for a formulation of a coccidia inhibitor that can be diluted in potable water to a dosage concentration of active substance in a short period of time without precipitation of the active substance.

The invention comprises: a) up to 10,000 ppm of active substance based on the formulation;

b) a water-miscible, physiologically acceptable anionic or nonionic surfactant or a mixture of several such surfactants; C) a physiologically acceptable surfactant based on the formulation; Water-soluble organic solvent 0-80g! d) 0 to 70% by weight of water, based on the formulation.

When the formulation according to the invention is diluted with potable water to a coccidia inhibitor dosage concentration of 1 to 500 ppm, preferably 2 to 1 ooppm, especially 2 to 60 ppm, the resulting aqueous active substance solution remains stable for a long time, i.e. up to several days. Remains stable for at least 24 hours. The usual concentration mentioned above,
That is, at a concentration of 0.5 to 5% by weight, it was then impossible to dissolve the active substance and form a stable aqueous solution. In fact, it was surprising that the solution was stable even if it was quite low. The concentration of the solubilizer in the drinking water, i.e. after diluting the active substance formulation according to the invention, is preferably 0.001 of the solubilizer.
~0.1% by weight, especially o,ooi ~0.01% by weight.

By using the water-miscible stock solutions (formulations) of the invention, it is industrially economical and easy to prepare stable aqueous solutions of active substances that could not otherwise be dissolved in water to give dosage concentrations. This provides a method that can be used in a variety of ways.

Of particular importance: Hl is hydrogen or O1-C4-alkyl, preferably hydrogen or methyl.

R2 together with R3 represents a double bond, or R2 and R5 each independently represent hydrogen or 01-C4
- alkyl, especially hydrogen or methyl.

Each X independently represents chlorine, bromine, 01-C4-alkyl,
Preferably methyl, trifluoromethyl or 01-C
4-Fulkoxy, n is 0.1 or 2, Y is hydrogen, 01-C4-halogenoalkyl, especially l8
-01-C3- having one or more fluorine atoms as a substituent
alkyl, phenyl, or at least one selected from the group consisting of methyl, methoxy, trifluoromethyl, chlorine, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl The above formula (1) is phenyl substituted with a group, and Z is a direct bond or oxygen.
The formulation of the invention contains the active substance of.

Preferred formulations of the invention are of formula (Ia): wherein R1 is hydrogen or methyl, R2 together with R3 represents a 21 bond, or R2 and R3 are each independently hydrogen or methyl; can be.

is hydrogen, chlorine or trifluoromethyl, and The active substance δ) is phenoxy, in particular 4-)tylsulfonylphenoxy.

Also particularly advantageous is that R and R' are each independently hydrogen or methyl, W is oxygen, and X is each independently chlorine, 01-C4-alkoxy, C1-C4-alkoxy,
~C4-alkyl or trifluoromethyl, and n is 0, 1 or 2.

Y is phenyl or phenyl substituted with at least one substituent selected from the group consisting of chlorine, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl; Yes, and.

A formulation according to the invention containing an active substance a) of formula (n) such that Z is oxygen.

Preferred formulations containing active substances a) of formula (II) are those of formula (It) in which R1 is hydrogen, R2 is methyl, W is oxygen and X is 6-methyl.

such that n is 1 and the group Y-Z- is the group 4-trifluoromethylthiophenoxy.

Adjuvants b) suitable for the formulations according to the invention are water-miscible;
Suitable non-ionic surfactants include, for example, anionic and non-ionic surfactants in which the active substance is dissolved in sufficient concentrations and physiologically acceptable.
CI2-01B fatty alcohol, CI2-CIFl fatty acid, 012-018 hydroxy fatty acid, C12-01
oligoethylene glycol ethers with compounds selected from the group consisting of 8-hydroxy fatty acid esters, sugar alcohols, sugar fatty acid esters, and other polyalcohols, such as glycerol, glycerol fatty acid esters, sorbitan fatty acid esters or glycerol/sorbitan fatty acid esters. It belongs to the group consisting of ethers or esters. Examples of these types of nonionic surfactants are POE sorbitan monolaurate, P
OE Sorbitol, POE Castor Oil, POE Hydrogenated Castor Oil, POE Lauryl Alcohol, POE Myristyl Alcohol, POE Cetyl Alcohol, POE Steary-2
2= /lz Flucor Oyohi POE Oleyl Alcohol.

POE glycerol/sorbitan fatty acid esters and POE fatty acid esters with fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid or oleic acid; represents one or more polyoxyethylene chains generally formed by

Preferred nonionic surfactants have an HLB greater than 14.
(hydrophilic/lipophilic balance). Preferred nonionic surfactants are poE sorbitan fatty acid esters, such as POE (20) sorbitan monolaurate (where each number within 0 indicates the total number of ethyleneoxy units contained in the surfactant molecule), POE ( 20)
sorbitan monostearate), POE(20) sorbitan monooleate), POE(20) sorbitan monopalmitate, as well as aliphatic alcohol oxyethylates such as POE(12) lauryl alcohol ether, POE(20) stearyl alcohol ether , P
OE (20) oleyl alcohol ether, POE (2
0) cetyl alcohol ether, POE(23) lauryl alcohol ether, and fatty acid oxyethylated compounds, such as POE(40) stearate or POE(50) stearate. Examples of anionic surfactants are sulfated fatty alcohols, fatty acid salts and fatty alcohol ether sulfates, preferably fatty alcohol ether sulfates such as sodium lauryl ether sulfate.

The formulations of the invention can contain up to 80% by weight of physiologically acceptable water-soluble organic solvents, based on the formulation.

Examples of suitable solvents are lower aliphatic alcohols such as ethyl alcohol and isopropyl alcohol, polyhydric alcohols such as glycerol, propylene glycol and polyethylene glycol, block copolymers of ethylene oxytodopropylene oxide, and aryl alkanols such as benzyl alcohol. be. Also suitable are ketones such as acetone and methyl ethyl ketone, or esters such as ethyl lactate.

In contrast to the water-miscible solution of West German patent application no. , which can be measured in the presence of residual moisture, but with a pH (lower than 8). After dilution with potable water to the dosage concentration, the potable water is substantially neutral or slightly acidic. and preferably has a pH of 6 to 7.

The formulations of the invention further contain preservatives, antioxidants, as well as suspension stabilizers, thickening agents such as methylcellulose and colloidal silica, and builders for livestock nutrition.
Other adjuvants such as colorants and Freno ζ-1 and physiologically resistant acids or buffers may also be included.

The proportion of these adjuvants is generally not more than 20% and preferably not more than 10% by weight of the formulation.

The formulation may contain water during manufacture, ie, even before dilution with water or potable water. This moisture content is common (=
It depends on the solubilizer used and the organic solvent used if appropriate. However, generally a water content of less than 10% by weight, based on the weight of the formulation, is preferred.

Preferred formulations according to the invention have the following components: a) 100 to 8000 pp of active substance of formula (1) or (It), based on the formulation; n, in particular 2000 to 6000 pp;
pprnlb) anionic or nonionic surfactants with an HLB number greater than 14; C) based on the formulation, physiologically acceptable water-soluble organic solvents from 0 to 60' d) 0-10% by weight of water, in particular 0-5.%, based on the formulation. Contains iJlchi.

The invention also relates to a process for the preparation of a formulation according to the invention, which comprises incorporating one or more active substances of formula (1) and (II) as defined above into a water-miscible physiologically acceptable anionic or non-water-miscible physiologically acceptable anionic system. in an ionic surfactant or a mixture of several of these surfactants, suitably in the presence of up to 80% of a physiologically acceptable water-soluble organic solvent based on the formulation; Based on the formulation, in the presence of up to 70! it% of water, the resulting formulation contains 10.00% of the active substance.
This includes containing up to D Dprn.

The formulations of the invention can be prepared, for example, by weighing all the ingredients of the formulation into a container and then stirring while heating until a clear solution is formed. It is also possible to use Solution F by stirring the mixture of components for a certain period of time, for example at an appropriately elevated temperature, and then filtering the mixture if a clear solution cannot be obtained without further filtration.

The invention furthermore relates to the use of the formulation according to the invention for the production of drinking water containing active substances for the treatment and prevention of coccidiosis in livestock, which means that the formulation according to the invention can be used in drinking water containing active substances for the treatment and prevention of coccidiosis in livestock. It includes adding to.

The amount of preparation added to drinking water varies depending on the efficacy of the particular coccidia inhibitor used, the species of bacteria, and the severity of the disease. As a rule, sufficient preparation is added to the drinking water such that the concentration of active substance in the drinking water is between 1 and 500 ppm, preferably between 2 and 1 o p'pm, especially between 2 and 30 ppm.

It is convenient to add the formulations of the invention to drinking water a relatively short time before use. The active substance formulations according to the invention have, in principle, a storage stability of several months. Dilute solutions prepared from neat formulations for administration as drinking water are generally stable for several days, but at least 24 hours.

In tests on livestock, drinking water prepared with the active substance formulations of the invention showed good tolerance and full medicinal efficacy.

Example 1 Formulation Formulas (D and (I) shown in Tables 1a) and ib) below
Using the active substances of I) and using the adjuvants and formulation ratios shown in Table 2, certain active substances were dissolved with heating.

Tables 1a) and 1b) a) Wl )a H--CI CF2HCF2-CF
2 1a H--C1l CF3-CHF-CF2
-0W3 Ta HHHC114-(CI(580
2) -C6H40-H4IaHCHt, HCA! 4
-(CH3SO2)-C6H40-H51a CH5
--CF5 HF6 1a CH3HHCF5 HF7 Ta
CH3--HCF3-CHF-CF2-0-b) Table 2 1 4 parts w1 1000 parts POE (20) Sorbitan monolaurate 21 parts W1 100 parts 31 parts W1 1000 parts 1 44 parts w2 1000 parts 54 parts w3 1000 parts 64 parts w4 1000 parts 74 parts w5 1000 parts 84 parts w6 1000 parts 94 parts w7 1000 parts 104 parts w8 1000 parts 111 parts w8 100 parts 121 parts W8 1000 parts 131 parts W3 1000 parts 146 parts w 11000 parts 154 parts w11 flno parts Lauryl sulfate Sodium ether 164 parts w3 1000 parts 174 parts w8 1000 parts Example Active substance 204 parts of a 1:1 mixture of surfactants W1 1000 parts poE(20) 228 mixture of sorbitan monolaurate and ethanol 214 Part w5 1000 parts POE (23) Lauryl alcohol 224 parts W5 1000 parts POE (20) Oleyl alcohol 234 parts "Ar1 1000 parts PO
E(20) Sorbitan Monooleate Example 2 Treatment For the treatment of coccidiosis in livestock, formulations 1-23
(Table 2) was diluted with water to obtain a dosage concentration, and administered to livestock by allowing them to drink water ad libitum.

Therapeutic trials include, for example, Elmer 1a
tenella) and Eimeria Acerbrina (Eime
ria acervulina) (Table 3) and susceptible strains of Eimeria tenella (Table 4).
) was used. 3 day old Lo kept in patagi
hmann-selected Leghorn chickens were allowed ad libitum access to medicated drinking water from D+2 (2nd day post-infection) to D+3. On the DO day (infected mortar), the treated group (12 birds/group) and the infected control group were specifically infected with I x 105 sporulated oocysts for each chicken. Group 1 was an uninfected control group that was not administered. Commercially available chicken feed was available ad libitum.

The coccidia suppressive effect and coccidiocidal effect were evaluated by examining the following numerical values (, r, JOhn
SOn, W, M, Re1d, rAnticoc
cidialDrugs:Lesion Scorin
g Techniques in Batter'ya
nd Floor-Pon Experiments
with Chictens.

Exp, Parasitol, (Anticoccidial drug: Impaired side constant force method in paternity/house test using chickens, parasitology experiment) J, 28.30-36 (19
70)).

Fecal findings on days D+4 and D+6 Measurement of mortality due to coccidiosis Weight gain = DO~D+7 days Macroscopic pathological damage in the intestinal tract (disability rating 20-4)
, D+4 to D+7 day results are shown in Tables 3 and 4.

The therapeutic effect is particularly clear since the mean value of gross pathological damage (disability rating 20-4) in the intestinal tract of chickens was lower than that of the infected control group. Similar results were obtained using other formulations in Table 2.

Claims (1)

[Claims] 1) The following ingredients: (a) Based on the weight of the preparation, formulas I and II: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) [In the formula, R^1, R and R' are each independently hydrogen or C_1-C_4-alkyl, and R^2 together with R^3 represents a double bond or itself independently hydrogen or C_1-C_4-alkyl; R^3 together with R^2 represents a double bond or itself independently hydrogen or C_1-C_4-alkyl; W is is oxygen or sulfur;
_4-alkylthio, nitro or C_1-C_4-alkoxy, n is 0, 1, 2, 3 or 4, preferably 0-2, Y is hydrogen, C_1-C_6-alkyl, C_1-C_6
- halogenoalkyl, benzyl, phenyl, or from the group consisting of alkyl, alkoxy, halogenoalkyl, halogenoalkoxy, halogen, alkylthio, alkylsulfinyl, alkylsulfonyl, halogenoalkylthio, halogenoalkylsulfinyl, and halogenoalkylsulfonyl at least one group selected with the proviso that each alkyl group is phenyl substituted with 1 to 4 carbon atoms, or is thienyl or halotienyl, and Z is a direct bond or has the formula O, S, SO, SO_2
, NH, NR^0 (however, R^0 is hydrogen or C_1~
C_4-alkyl), or C(C
(b) a water-miscible, physiologically acceptable anionic system; or a nonionic surfactant or a mixture of several such surfactants; (c) 0 to 80% by weight, based on the formulation, of a physiologically acceptable water-soluble organic solvent; (d) the formulation Active substance preparations containing from 0 to 70% by weight, based on water. 2) R^1 is hydrogen or C_1-C_4-alkyl, preferably hydrogen or methyl, R^2 together with R^3 represents a double bond, or R^2 and R^3 are Each independently, hydrogen or C_1
~C_4-alkyl, especially hydrogen or methyl; each X is independently chlorine, bromine, C_1-C_4-alkyl, preferably methyl, trifluoromethyl or C_4-alkyl;
1-C_4-alkoxy, n is 0, 1 or 2, Y is hydrogen, C_1-C_4-halogenoalkyl, especially C_1-C_3-alkyl having one or more fluorine atoms as substituent, phenyl, or ,
phenyl substituted with at least one group selected from the group consisting of methyl, methoxy, trifluoromethyl, chlorine, methylthio, methylsulfinyl, methylsulfonyl, trifluoromethylthio, trifluoromethylsulfinyl or trifluoromethylsulfonyl, An active substance preparation according to claim 1 containing an active substance of formula (I) according to claim 1, wherein Z is a direct bond or oxygen. 3) R and R' are each independently hydrogen or methyl, W is oxygen, and X is each independently chlorine, C_1-C_4-alkoxy,
C_1-C_4-alkyl or trifluoromethyl, n is 0, 1 or 2, Y is phenyl, or chlorine, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, trifluoromethylsulfinyl or Claim 1 or 2 containing an active substance of formula II of claim 1, wherein phenyl is substituted with at least one substituent selected from the group consisting of trifluoromethylsulfonyl, and Z is oxygen.
Active substance preparations as described. 4) Formula (I a): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I a) [In the formula, R^1 is hydrogen or methyl, and R^2 together with R^3 forms a double bond. or R^2 and R^3 are each independently hydrogen or methyl, X' is hydrogen, chlorine or trifluoromethyl, and Y-Z- is hydrogen, C_1-C_4- 4. The active substance a) is halogenoalkoxy, in particular tetrafluoroethoxy or hexafluoropropoxy, or C_1-C_4-alkylsulfonylphenoxy, especially 4-methylsulfonylphenoxy.
Active substance preparations according to one or more of the above. 5) The following ingredients: (a) 100 to 8000 ppm of active substance of formula (I) or (II), based on the formulation; (b) anionic or nonionic surfactant with an HLB number greater than 14; (c) 0-60% by weight of a physiologically acceptable water-soluble organic solvent, based on the formulation; (d) 0-10% by weight of water, based on the formulation. Active substance formulation according to one or more of the above. 6) The nonionic surfactant contains oligopolyglycol ether, C_1_2 to C_1_8-fatty acids, and C_1_
2~C_1_8 aliphatic alcohol, C_1_2~C_1
Active substance formulation according to one or more of claims 1 to 5, which is a surfactant selected from the group of _8 hydroxy fatty acids and esters, sugar alcohols and ethers or esters with sugar fatty acid esters. 7) An active substance preparation according to claim 6, wherein the surfactant is an oxyethylate of sorbitan fatty acid ester. 8) one or more active substances of formulas (I) and (II) as defined above in a water-miscible physiologically acceptable anionic or nonionic surfactant or a mixture of several of these surfactants; suitably in the presence of up to 80% by weight of a physiologically acceptable water-soluble organic solvent based on the formulation, and suitably in the presence of up to 70% by weight of water based on the formulation, The resulting formulation contains 10,000 active substances.
8. Process for producing an active substance formulation according to one or more of claims 1 to 7, comprising containing up to ppm. 9) Use of an active substance formulation according to at least one of claims 1 to 7 for the preparation of drinking water for the treatment of coccidiosis in livestock. 10) The use according to claim 9, wherein the preparation is diluted with water to an active substance content of 1 to 500 ppm.